Tyrosine-specific Protein Kinases (PTKs) are a family of enzymes which catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues in protein substrates [for review see: Hunter, T; Protein modification: phosphorylation on tyrosine residue; Curr Opin Cell Biol 1989; 1: 1168-1181]. The first members of this class of enzymes to be identified were PTKs encoded by viral oncogenes, which were capable of cell transformation (ie. pp6Ov-src and pp98v-fps). Later it was shown that there were normal cellular counterparts of these viral gene products (ie. pp60C-src and pp98c-fps). Since that discovery, a large number of genes encoding PTKs have been identified [for review see Hunter, T; Protein kinase classification; Methods Enzymol 1991; 200:3-37]. These include growth factor receptor PTKs such as the insulin and epidermal growth factor receptors, as well as non-receptor PTKs such as ZAP-70 and Lck. Although the molecular details have yet to be fully elucidated, PTK-mediated phosphorylation of tyrosine residues on protein substrates leads to the transduction of intracellular signals that regulate a variety of intracellular processes such as growth, transport, motility, and senescence. Many disease states are dependent on these cellular functions. Therefore, inhibitors of tyrosine kinases are useful for the prevention and chemotherapy of disease states that are dependent on these enzymes.
For example, tyrosine kinase inhibitors are useful for inhibiting T-cell activation and thus they are useful as immunosuppressive agents for the prevention or treatment of graft rejection following transplant surgery and for the prevention or treatment of autoimmune diseases such as rheumatoid arthritis and psoriasis. Graft rejection following transplant surgery is a common occurrence which arises when foreign antigens are recognized by the host immune system. In an effort to protect itself from the foreign tissue, the host immune system is then activated to release an arsenal of antibodies, soluble lymphokines, and cytotoxic lymphocytes which attack the foreign tissue, resulting in complications which often end in graft rejection. Similarly, a breakdown in self-tolerance can result in immune system attacks against the body""s own tissues. These attacks can lead to autoimmune and chronic inflammatory diseases. Since T cells are the key regulators of these immune system attacks, inhibitors of T cell activation are useful therapeutic agents.
Currently the leading medicinal agent for the prevention or treatment of graft rejection is Cyclosporin A, approved by the United States Food and Drug Administration in 1983. Cyclosporin A is extremely effective at preventing transplant rejection and is efficacious in the treatment of autoimmune disorders such psoriasis, rheumatoid arthritis, inflammatory bowel disease, and type I diabetes. It work by forming complexes with a specific protein which can then inhibit the catalytic activity of calcineurin, a phosphatase that plays a key role in transducing signals from the T cell receptor (TcR) to the nucleus. However, calcineurin is ubiquitously expressed and is involved in many other signal transduction pathways. As a result, Cyclosporin A suffers drawbacks in that it can cause kidney failure, liver damage and ulcers; which in many cases can be very severe. Consequently, Cyclosporin A has a very narrow therapeutic index and is rarely used to treat chronic autoimmune diseases. Safer drugs which are more selective in their ability to affect the immune response system and which have fewer side effects are constantly being pursued. Thus, there is a continuing need and a continuing search in this field of art for alternative therapies. The Src-family protein tyrosine kinase, Lck, is upstream of calcineurin in the TcR-mediated signaling cascade. Lck is expressed almost exclusively in T cells and its catalytic activity is required for T cell signal transduction [for review see: Anderson S J, Levin S D, Perlmutter, R M; Involvement of the protein tyrosine kinase p56lck in T cell signaling and thymocyte development; Adv Immunol 1994; 56:151-178]. Thus, a potent Lck-selective kinase inhibitor would make a promising drug candidate.
Lck is one of 8 known members of the human Src-family of protein tyrosine kinases. The other members are Src, Fyn, Lyn, Fgr, Hck, Blk, and Yes. As a consequence of alternative mRNA splicing, Fyn exists as two distinct gene products, Fyn(T) and Fyn(B), that differ at their ATP binding sites. All Src-family kinases contain an N-terminal myristoylation site followed by a unique domain characteristic of each individual kinase, an SH3 domain that binds proline-rich sequences, an SH2 domain that binds phosphotyrosine-containing sequences, a linker region, a catalytic domain, and a C-terminal tail containing an inhibitory tyrosine. The activity of Src-family kinases is tightly regulated by phosphorylation. Two kinases, Csk and Ctk, can down-modulate the activity of Src-family kinases by phosphorylation of the inhibitory tyrosine. This C-terminal phosphotyrosine can then bind to the SH2 domain via an intramolecular interaction. In this closed state, the SH3 domain binds to the linker region, which then adopts a conformation that impinges upon the kinase domain and blocks catalytic activity. Dephosphorylation of the C-terminal phosphotyrosine by intracellular phosphatases such as CD45 and SHP-1 can partially activate Src-family kinases. In this open state, Src-family kinases can be fully activated by intermolecular autophosphorylation at a conserved tyrosine within the activation loop.
Src-family kinases display a variety of tissue-specific expression patterns. Src, Fyn(B), Yes, and Lyn are found in a broad range of tissues with especially high levels of expression in neuronal and hematopoietic cells. The expression of these particular Src-family kinases overlap to a great extent, however no cell types have been found that express all four of them. Expression of Lck, Fyn(T), Fgr, Hck, and BIk is restricted to cells of the hematopoietic lineage. In general, myeloid cells co-express Hck, Fgr, and Lyn; immature B cells co-express Hck, Lyn, and Blk; and mature B cells co-express Hck, Lyn, Blk, Fgr, and Fyn(T). T cells predominantly express Lck and Fyn(T). Lck is also expressed in NK cells.
A complex cascade of biochemical events mediates signal transduction in T cells [for review see: Chan A C, Desai D M, Weiss A; The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction; Annu Rev Immunol 1994;12:555-592]. While many proteins involved in this signaling cascade have been identified, the molecular details of this process are just beginning to be unraveled. The antigen-specific xcex1/xcex2 TcR heterodimer is noncovalently associated with CD3-xcex5, -xcex4 and xcex6 polypeptide chains. In the current paradigm of T cell activation, stimulation of the TcR by MHC/peptide complexes on the surface of antigen presenting cells (APCs) leads to the rapid activation of Lck. Activated Lck then phosphorylates CD3 and xcex6 proteins on tyrosine residues within conserved motifs known as ITAMs (Immunoreceptor-associated Tyrosine-based Activation Motifs). Another protein tyrosine kinase, ZAP-70, is recruited to the TcR complex via association of its tandem pair of SH2 domains to doubly phosphorylated ITAMs. Lck, in turn, activates TcR-associated ZAP-70 by phosphorylation of tyrosine 493 in the ZAP-70 activation loop. Activated ZAP-70 goes on to phosphorylate a variety of downstream adapter molecules such as LAT, SLP-76, and HS1. Lck can also phosphorylate additional protein substrates in activated T cells. One important substrate is Vav, a guanine nucleotide exchange protein that is regulated by Lck phosphorylation. Activated Vav mediates GDP release by Rac/Rho family members which, in turn, leads to the reorganization of the actin cytoskeleton, an event that is necessary for T cell activation. In addition to TcR recognition of MHC/peptide complexes on the surface of APCs, there are many co-receptor pairs that are important in T cell-APC interactions. Of note are CD4 and CD8, which are associated with Lck and bind to nonpolymorphic regions of MHC Class II and Class I molecules, respectively. Other co-receptor pairs include CD28/B7, CTLA-4/B7, LFA-2/LFA-3, LFA-1/ICAM, CD40/CD40L, SLAM/SLAM, and etc./etc. This vast array of cell-cell molecular interactions stabilizes T cell/APC conjugates and initiates additional intracellular signaling cascades. Signals derived from co-receptor engagement are integrated with signals derived from stimulation of the TcR to determine the magnitude and the quality of the T cell response.
Genetic data clearly validate Lck as an excellent therapeutic target. Mice in whom Lck expression was perturbed by either genetic deletion or by overexpression of a catalytically inactive version of Lck exhibited an early block in T cell development. The small number of mature T cells in the periphery of Lck-deficient mice were inefficient at transducing signals from the TcR and could not mediate a vigorous response to antigenic challenge. NK cells from Lck deficient mice appeared to function normally. No functional defects outside of the immune system were noted in these animals. In addition there is a report in the literature of a human patient with low levels of Lck expression due to an inability to properly splice Lck mRNA [see: Goldman F D, Ballas Z K, Schutte B C, Kemp J, Hollenback C, Noraz N, Taylor N.; Defective expression of p56lck in an infant with severe combined Immunodeficiency; J Clin Invest 1998; 102:421-429]. This patient presented with Severe Combined Immunodeficiency Syndrome (SCID). Again, no other phenotypic disturbances outside of this immune system disorder were noted. These results strongly suggest that Lck inhibitors would be effective in suppressing T cell mediated immune responses without causing mechanism-based toxicity.
The present invention provides substituted pyrimidine compounds of formula I: 
or a pharmaceutically acceptable salt, hydrate, solvate, crystal form or individual diastereomers thereof (as defined below), for use as a protein tyrosine kinase inhibitor. The invention also includes the use the compounds of formula I in the prophylaxis and treatment of immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to have a role.

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein
R1 and R2 are independently:
a) H,
b) halo (Br, Cl, I, or F)
c) OH,
d) SH,
e) CN,
f) NO2,
g) R11,
h) OR11,
i) OC(xe2x95x90O)R11,
j) OC(xe2x95x90O)OR11,
k) OC(xe2x95x90O)NHR11,
l) OC(xe2x95x90O)NR11R12,
m) SR11,
n) SOR11,
o) SO2R11,
p) C(xe2x95x90O)R11,
q) C(xe2x95x90O)ORI1,
r) C(xe2x95x90O)NHR11,
s) C(xe2x95x90O)NR11R12,
t) NH2,
u) NHR11,
v) NRR11R12,
w) NHC(xe2x95x90O)R11,
x) NR11C(xe2x95x90O)R12,
y) NR11C(xe2x95x90O)NHR12,
z) NR11C(xe2x95x90O)NR12R13,
aa) SO2NHR11,
ab) SO2NR11R12,
ac) NHSO2R11,
ad) NR11SO2R12,
ae) R1 and R2 can join together to form a fused methylenedioxy ring or a fused 6-membered aromatic ring;
R3 and R5 independently are:
a) H,
b) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
c) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substituents selected from: Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2, or
d) R3 and R5 taken together can represent xe2x95x90O;
e) R3 or R5 can represent a 2 or 3 carbon methylene bridge forming a ring of 5 to 8 atoms fused to the A ring;
R4 is:
a) H, or
b) C1-C6-alkyl, or
c) C1-C6-alkoxyl;
X5 and X6 are independently CRa or N;
Ra is: absent, H, or C1-C6-alkyl;
n is 0, 1 or 2;
xe2x80x94X1xe2x80x94X2xe2x80x94X3xe2x80x94X4xe2x80x94 is:
a) xe2x80x94CR6xe2x95x90CR6xe2x80x94CR6axe2x95x90CR6xe2x80x94,
b) xe2x80x94CR6axe2x95x90CR6xe2x80x94CR6xe2x95x90CR6xe2x80x94,
c) xe2x80x94CR6xe2x95x90CR6axe2x80x94CR6xe2x95x90CR6xe2x80x94,
d) xe2x80x94CR6xe2x95x90CR6xe2x80x94CR6xe2x95x90CR6axe2x80x94,
e) xe2x80x94Nxe2x95x90CR6xe2x80x94CR6xe2x95x90CR6xe2x80x94,
f) xe2x80x94CR6xe2x95x90Nxe2x80x94CR6xe2x95x90CR6xe2x80x94,
g) xe2x80x94CR6xe2x95x90CR6xe2x80x94Nxe2x95x90CR6xe2x80x94,
h) xe2x80x94CR6xe2x95x90CR6xe2x80x94CR6xe2x95x90Nxe2x80x94,
i) xe2x80x94Nxe2x95x90CR6xe2x80x94Nxe2x95x90CR6xe2x80x94,
j) xe2x80x94CR6xe2x95x90Nxe2x80x94CR6xe2x95x90Nxe2x80x94,
k) xe2x80x94CR6xe2x95x90Nxe2x80x94Nxe2x95x90CR6xe2x80x94, or
l ) xe2x80x94Nxe2x95x90CR6xe2x80x94CR6xe2x95x90Nxe2x80x94;
R6 and R6a are independently:
a) H,
b) halo( Br, Cl, I, or F)
c) OH,
d) SH,
e) CN,
f) NO2,
g) N3,
h) N2+BF4xe2x88x92,
i) R11,
j) OR11,
k) OC(xe2x95x90O)R11,
l) OC(xe2x95x90O)OR11,
m) OC(xe2x95x90O)NHR11,
n) OC(xe2x95x90O)NR11R12,
o) SR11,
p) SOR11,
q) SO2R11,
r) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11,R12, and R13,
s) C(xe2x95x90O)R11,
t) C(xe2x95x90O)OR11,
u) C(xe2x95x90O)NHR11,
v) C(xe2x95x90O)NR11R11R12,
w) C(xe2x95x90O)N(OR11)R12,
x) NH2,
Y) NHR11,
z) NHC1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11,R12, and R13,
aa) NR11R12,
ab) NHC(xe2x95x90O)R11,
ac) NR11C(xe2x95x90O)R12,
ad) NHC(xe2x95x90O)NHR11,
ae) NR11C(xe2x95x90O)NHR12,
af) NR11C(xe2x95x90O)NR12R13,
ag) SO2NH2,
ah) SO2NHR11,
ai) SO2NR11R12,
aj) NHSO2R11,
ak) NR11SO2R12,
al) NHP(xe2x95x90O)(OC1-C6-alkyl)2, or
am) R6 and R6a when on adjacent carbons can be joined to form a 5- or 6-membered ring having the following bridging atoms:
i) xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94,
ii) xe2x80x94OCH2Oxe2x80x94,
iii) xe2x80x94C(O)N(R11)C(O)xe2x80x94,
iv) xe2x80x94CH2N(R11)CH2xe2x80x94,
v) xe2x80x94Nxe2x95x90CHNHC(O)xe2x80x94,
vi) xe2x80x94C(O)NHCHxe2x95x90Nxe2x80x94,
vii) xe2x80x94C(O)OC(O)xe2x80x94,
viii) xe2x80x94NHC(O)NHC(O)xe2x80x94,
ix) xe2x80x94C(O)NHC(O)NHxe2x80x94,
x) xe2x80x94Nxe2x95x90CHNHxe2x80x94,
xi) xe2x80x94NHCHxe2x95x90Nxe2x80x94,
xii) xe2x80x94Nxe2x95x90CHNR11xe2x80x94,
xiii) xe2x80x94NR11CHxe2x95x90Nxe2x80x94,
xiv) 
xv) 
xe2x80x83represents:
a) phenyl,
b) naphthyl,
c) pyridyl,
d) pyrazinyl,
e) pyrimidinyl,
f) pyrroly),
g) thienyl,
h) oxazolyl,
i) isoxazolyl,
j) thiazolyl,
k) pyrazolyl,
l) triazolyl,
m) tetrazolyl,
n) furanyl,
o) benzothienyl,
p) benzofuranyl,
q) indolyl,
r) imidazolyl,
s) benzimidazolyl, or
t) thiadiazolyl,
R7, R8, R9, and R10 independently are selected from:
a) H,
b) halo( Br, Cl, I, or F)
c) OH,
d) SH,
e) CN,
f) NO2,
g) N3 
h) N2+BF4xe2x88x92
i) R11,
j) OR11,
k) SR11,
l) SOR11,
m) SO2R11,
n) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11, R12, and R13,
o) C1-C6-perfluoroalkyl,
p) C(xe2x95x90O)R11,
q) C(xe2x95x90O)OR11,
r) C(xe2x95x90O)NHR11,
s) C(xe2x95x90O)NR11R12,
t) NH2,
u) NHR11,
v) NHC1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11,R12, and R13,
w) NR11R12,
x) NHC(xe2x95x90O)R11,
y) NR11C(xe2x95x90O)R12,
z) NR11C(xe2x95x90O)NHR12,
aa) NR11C(xe2x95x90O)NR12R13,
ab) SO2NHR11,
ac) SO2NR11R12,
ad) NHSO2R11,
ae) NR11SO2R12, or
af) two of R7, R8, R9, and R10 when on adjacent carbons join together to form a methylenedioxy bridge;
R11, R12, and R13 independently are selected from:
a) C1-C6-perfluoroalkyl,
b) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
c) C2-C6-alkenyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
d) C2-C6-alkynyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
e) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, or three substituents selected from Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
f) heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with one, two, three or four substituents selected from oxo, Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2, or
g) C3-C6-cycloalkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2;
Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2 independently are selected from:
a) H,
b) halo,
c) CN,
d) NO2,
e) hydroxy,
f) C1-C6-perfluoroalkyl,
g) C1-C6-alkoxyl, alkoxyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,
h) (Cxe2x95x90O)(C1-C6-alkyl), alkyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,
i) (Cxe2x95x90O)O(C1-C6-alkyl), alkyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,
j) (Cxe2x95x90O)NH(C1-C6-alkyl),
k) (Cxe2x95x90O)N(C1-C6-alkyl)2,
l) NH2,
m) NHC1-C6-alkyl, wherein alkyl is unsubstituted or substituted with aryl or NH2,
n) N(C1-C6-alkyl)2,
o) NHaryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, or three substituents selected from halo, phenyl, CN, NO2, hydroxy, C1-C6-alkyl, C1-C6-alkoxyl, NH2, NHC1-C6-alkyl, N(C1-C6-alkyl)2, (Cxe2x95x90O)(C1-C6-alkyl), (Cxe2x95x90O)O(C1-C6-alkyl), (Cxe2x95x90O)NH(C1-C6-alkyl), (Cxe2x95x90O)N(C1-C6-alkyl)2, NH(Cxe2x95x90O)(C1-C6-alkyl),
p) NHheterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from halo, phenyl, oxo, CN, NO2, hydroxy, C1-C6-alkyl, C1-C6-alkyl substituted with C3-C7-cycloalkyl, C1-C6-alkoxyl, NH2, NHC1-C6-alkyl, N(C1-C6-alkyl)2, (Cxe2x95x90O)(C1-C6-alkyl), (Cxe2x95x90O)O(C1-C6-alkyl), (Cxe2x95x90O)OCH2phenyl, (Cxe2x95x90O)NH(C1-C6-alkyl), (Cxe2x95x90O)N(C1-C6-alkyl)2, NH(Cxe2x95x90O)(C1-C6-alkyl),
q) NHCHO,
r) NH(Cxe2x95x90O)(C1-C6-alkyl),
s) NH(Cxe2x95x90O)(OC1-C6-alkyl),
t) aryl, wherein aryl is as defined above in o,
u) C1-C6-alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, C3-C7-cycloalkyl, aryl or heterocyclyl, wherein aryl is defined as above in o and heterocyclyl is as defined above in p,
v) heterocyclyl, wherein heterocyclyl is as defined above in p,
w) when two of Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2 are on adjacent carbons they can join to form a methylenedioxy bridge,
x) NH(Cxe2x95x90O)aryl,
y) xe2x80x94NR14NHR15,
z) xe2x80x94S(O)x C1-C6-alkyl,
aa) SO2NH C1-C6-alkyl, or
ab) CO2H;
R14 and R15 are independently: H, C1-C6-alkyl, aryl or C1-C6-alkylaryl; or
x is 0, 1 or 2.
An embodiment of the invention is the compound of Formula I 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein
R1 and R2 are independently:
a) H,
b) halo (Br, Cl, I, or F)
c) OH,
d) SH,
e) CN,
f) NO2,
g) R11,
h) OR11,
i) OC(xe2x95x90O)R11,
j) OC(xe2x95x90O)OR11,
k) OC(xe2x95x90O)NHR11,
l ) OC(xe2x95x90O)NR11R12,
m) SR11,
n) SOR11,
o) SO2R11,
p) C(xe2x95x90O)R11,
q) C(xe2x95x90O)OR11,
r) C(xe2x95x90O)NHR11,
s) C(xe2x95x90O)NR11R12,
t) NH2,
u) NHR11,
v) NR11R12,
w) NHC(xe2x95x90O)R11,
x) NR11C(xe2x95x90O)R12,
y) NR11C(xe2x95x90O)NHR12,
z) NR11C(xe2x95x90O)NR12R13,
aa) SO2NHR11,
ab) SO2NR11R12,
ac) NHSO2R11,
ad) NR11SO2R12,
ae) R1 and R2 can join together to form a fused methylenedioxy ring or a fused 6-membered aromatic ring;
R3 and R5 independently are:
a) H,
b) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
c) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substituents selected from: Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2, or
d) R3 and R5 taken together can represent xe2x95x90O;
e) R3 or R5 can represent a 2 or 3 carbon methylene bridge forming a ring of 5 to 8 atoms fused to the A ring;
R4 is:
a) H, or
b) C1-C6-alkyl, or
c) C1-C6-alkoxyl;
X5 and X6 are independently CRa or N;
Ra is: absent, H, or C1-C6-alkyl;
n is 0, 1 or 2;
xe2x80x94X1xe2x80x94X2xe2x80x94X3xe2x80x94X4xe2x80x94 is:
a) xe2x80x94CR6xe2x95x90CR6xe2x80x94CR6axe2x95x90CR6xe2x80x94,
b) xe2x80x94CR6axe2x95x90CR6xe2x80x94CR6xe2x95x90CR6xe2x80x94,
c) xe2x80x94Nxe2x95x90CR6xe2x80x94CR6xe2x95x90CR6xe2x80x94,
d) xe2x80x94CR6xe2x95x90Nxe2x80x94CR6xe2x95x90CR6xe2x80x94,
e) xe2x80x94CR6xe2x95x90CR6xe2x80x94Nxe2x95x90CR6xe2x80x94,
f) xe2x80x94CR6xe2x95x90CR6xe2x80x94CR6xe2x95x90Nxe2x80x94,
g) xe2x80x94Nxe2x95x90CR6xe2x80x94Nxe2x95x90CR6xe2x80x94,
h) xe2x80x94CR6xe2x95x90Nxe2x80x94CR6xe2x95x90Nxe2x80x94,
i) xe2x80x94CR6xe2x95x90Nxe2x80x94Nxe2x95x90CR6xe2x80x94, or
j) xe2x80x94Nxe2x95x90CR6xe2x80x94CR6xe2x95x90Nxe2x80x94;
R6 and R6a are independently:
a) H,
b) halo( Br, Cl, I, or F)
c) OH,
d) SH,
e) CN,
f) NO2,
g) N3,
h) N2+BF4xe2x88x92,
i) R11,
j) OR11,
k) OC(xe2x95x90O)R11,
l) OC(xe2x95x90O)OR11
m) OC(xe2x95x90O)NHR11,
n) OC(xe2x95x90O)NR11R12,
o) SR11,
p) SOR11,
q) SO2R11,
r) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11, R12, and R13,
s) C(xe2x95x90O)R11,
t) C(xe2x95x90O)OR11,
u) C(xe2x95x90O)NHR11,
v) C(xe2x95x90O)NR11R12,
w) C(xe2x95x90O)N(OR11)R12,
x) NH2,
Y) NHR11,
z) NHC1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11, R12, and R13,
aa) NR11R12,
ab) NHC(xe2x95x90O)R11,
ac) NR11C(xe2x95x90O)R12,
ad) NHC(xe2x95x90O)NHR11,
ae) NR11C(xe2x95x90O)NHR12,
af) NR11C(xe2x95x90O)NR12R13,
ag) SO2NH2,
ah) SO2NHR11,
ai) SO2NR11R12,
aj) NHSO2R11,
ak) NR11SO2R12,
al) NHP(xe2x95x90O)(OC1-C6-alkyl)2, or
am) R6 and R6a when on adjacent carbons can be joined to form a 5- or 6-membered ring having the following bridging atoms:
i) xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94,
ii) xe2x80x94OCH2Oxe2x80x94,
iii) xe2x80x94C(O)N(R11)C(O)xe2x80x94,
iv) xe2x80x94CH2N(R11)CH2xe2x80x94,
v) xe2x80x94Nxe2x95x90CHNHC(O)xe2x80x94,
vi) xe2x80x94C(O)NHCHxe2x95x90Nxe2x80x94,
vii) xe2x80x94C(O)OC(O)xe2x80x94,
viii) xe2x80x94NHC(O)NHC(O)xe2x80x94,
ix) xe2x80x94C(O)NHC(O)NHxe2x80x94,
x) xe2x80x94Nxe2x95x90CHNHxe2x80x94, or
xi) xe2x80x94Nxe2x95x90CHNR11xe2x80x94, or
xii) 
xe2x80x83represents:
a) phenyl,
b) naphthyl,
c) pyridyl,
d) pyrazinyl,
e) pyrimidinyl,
f) pyrrolyl,
g) thienyl,
h) oxazolyl,
i) isoxazolyl,
j) thiazolyl,
k) pyrazolyl,
l) triazolyl,
m) tetrazolyl,
n) furanyl,
o) benzothienyl,
p) benzofuranyl,
q) indolyl,
r) imidazolyl,
s) benzimidazolyl, or
t) thiadiazolyl,
R7, R8, R9, and R10 independently are selected from:
a) H,
b) halo( Br, Cl, I, or F)
c) OH,
d) SH,
e) CN,
f) NO2,
g) N3 
h) N2+BF4xe2x88x92
i) R11,
j) OR11,
k) SR11,
l) SOR11,
m) SO2R11,
n) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11, R12, and R13,
o) C1-C6-perfluoroalkyl,
p) C(xe2x95x90O)R11,
q) C(xe2x95x90O)OR11,
r) C(xe2x95x90O)NHR11,
s) C(xe2x95x90O)NR11R12,
t) NH2,
u) NHR11,
v) NHC1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11, R12, and R13,
w) NR11R12,
x) NHC(xe2x95x90O)R11,
y) NR11C(xe2x95x90O)R12,
z) NR11C(xe2x95x90O)NHR12,
aa) NR11C(xe2x95x90O)NR12R13,
ab) SO2NHR11,
ac) SO2NR11R12,
ad) NHSO2R11,
ae) NR11SO2R12, or
af) two of R7, R8, R9, and R10 when on adjacent carbons join together to form a methylenedioxy bridge;
R11, R12, and R13 independently are selected from:
a) C1-C6-perfluoroalkyl,
b) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
c) C2-C6-alkenyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
d) C2-C6-alkynyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
e) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, or three substituents selected from Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
f) heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2;
g) C3-C6-cycloalkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2 independently are selected from:
a) H,
b) halo,
c) CN,
d) NO2,
e) hydroxy,
f) C1-C6-perfluoroalkyl,
g) C1-C6-alkoxyl, alkoxyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,
h) (Cxe2x95x90O)(C1-C6-alkyl), alkyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,
i) (Cxe2x95x90O)O(C1-C6-alkyl), alkyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,
j) (Cxe2x95x90O)NH(C1-C6-alkyl),
k) (Cxe2x95x90O)N(C1-C6-alkyl)2,
l) NH2,
m) NHC1-C6-alkyl,
n) N(C1-C6-alkyl)2,
o) NHaryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, or three substituents selected from halo, phenyl, CN, NO2, hydroxy, C1-C6-alkyl, C1-C6-alkoxyl, NH2, NHC1-C6-alkyl, N(C1-C6-alkyl)2, (Cxe2x95x90O)(C1-C6-alkyl), (Cxe2x95x90O)O(C1-C6-alkyl), (Cxe2x95x90O)NH(C1-C6-alkyl), (Cxe2x95x90O)N(C1-C6-alkyl)2, NH(Cxe2x95x90O)(C1-C6-alkyl),
p) NHheterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from halo, phenyl, oxo, CN, NO2, hydroxy, C1-C6-alkyl, C1-C6-alkoxyl, NH2, NHC1-C6-alkyl, N(C1-C6-alkyl)2, (Cxe2x95x90O)(C1-C6-alkyl), (Cxe2x95x90O)O(C1-C6-alkyl), (Cxe2x95x90O)OCH2phenyl, (Cxe2x95x90O)NH(C1-C6-alkyl), (Cxe2x95x90O)N(C1-C6-alkyl)2, NH(Cxe2x95x90O)(C1-C6-alkyl),
q) NHCHO,
r) NH(Cxe2x95x90O)(C1-C6-alkyl),
s) NH(Cxe2x95x90O)(OC1-C6-alkyl),
t) aryl, wherein aryl is as defined above in o,
u) C1-C6-alkyl, wherein alkyl is unsubstituted or substituted with aryl or heterocyclyl, wherein aryl is defined as above in o and heterocyclyl is as defined above in p,
v) heterocyclyl, wherein heterocyclyl is as defined above in p, or
w) when two of Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2 are on adjacent carbons they can join to form a methylenedioxy bridge.
Preferred compounds of the present invention include the compound of Formula Ia: 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R1, R2, and R3 are as defined below and all other substituents are as defined above,
R1 and R2 are independently:
a) H,
b) R11,
c) NH2,
d) NHR11, or
e) NR11R12; and
R3 is:
a) H, or
b) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2.
Preferred compounds of the present invention include the compound of Formula Ib: 
or a pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R1 and xe2x80x94X1xe2x80x94X2xe2x80x94X3xe2x80x94X4xe2x80x94 are as defined below and all other substituents are as defined above,
R1is:
a) H,
b) R11,
c) NH2,
d) NHR11, or
e) NR11R12; and
xe2x80x94X1xe2x80x94X2xe2x80x94X3xe2x80x94X4xe2x80x94 is:
a) xe2x80x94CR6xe2x95x90CR6xe2x80x94CR6axe2x95x90CR6xe2x80x94,
b) xe2x80x94CR6axe2x95x90CR6xe2x80x94CR6xe2x95x90CR6xe2x80x94,
c) xe2x80x94CR6xe2x95x90Nxe2x80x94CR6xe2x95x90CR6xe2x80x94, or
d) xe2x80x94CR6xe2x95x90CR6xe2x80x94Nxe2x95x90CR6xe2x80x94.
Preferred compounds of the present invention include the compounds of Formula Ic: 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R6 and R6a are as defined below and all other substituents are as defined above,
R6 and R6a are independently:
a) H,
b) halo (Br, Cl, I, or F),
c) R11,
d) OR11,
e) C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R9, R10, and R11,
f) NH2,
g) NHR11,
h) NHC1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R9, R10, and R11,
i) NR11R12,
j) NHC(xe2x95x90O)R11,
k) NR11C(xe2x95x90O)R12,
l) NR11C(xe2x95x90O)NHR12,
m) NR11C(xe2x95x90O)NR12R13,
n) NHSO2R11,
o) NR11SO2R12, or
p) R6 and R6a when on adjacent carbons can be joined to form a 5- or 6-membered ring having the following bridging atoms, when read from right to left, or left to right:
i) xe2x80x94Nxe2x95x90CHNHxe2x80x94,
ii) xe2x80x94Nxe2x95x90CHNR11xe2x80x94, or
iii) 
Preferred compounds of the present invention include those of Formula Ic: 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R1 is H, aryl, or heterocyclyl, and all other substituents are as defined above.
Preferred compounds of the present invention include those of Formula Ic: 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein A is defined as phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thiadiazolyl, and all other substituents are as defined above.
Preferred compounds of the present invention include those of Formula Id: 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein all substituents are as defined above, except that R6 is attached to the 5- or 6-position of the benzimidazole.
Preferred compounds of the present invention include those of Formula Ie: 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R6 is as defined below and all other substituents are as defined above,
R6 is:
a) H,
b) phenyl, unsubstituted or substituted with one, two, or three substituents selected from Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
c) pyridyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
d) pyridazinyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
e) pyriridinyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
f) thiazolyl, unsubstituted or substituted with one, two, or three substituents selected from Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
g) thiadiazolyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
h) thienyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
i) pyrazinyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
j) imidazolyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
k) imidazolidinyl, unsubstituted or substituted with one, two or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
l) 1,3-diazobicyclo[3.3.0]octan-2-onyl,
m) 1,3-diazobicyclo[4.3.0]nonan-2-onyl,
n) NH2,
o) NHR8,
p) NHC1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R8, R9, and R10,
q) NR8R9,
r) NHC(xe2x95x90O)R8,
s) NR8C(xe2x95x90O)R9,
t) NR8C(xe2x95x90O)NHR9,
u) NR8C(xe2x95x90O)NR9R10,
v) NHSO2R8, or
w) NR8SO2R9.
Preferred compounds of the present invention include those of Formula If: 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R6 is as defined below and all other substituents are as defined above,
R6 is:
a) H,
b) phenyl, unsubstituted or substituted with one, two, or three substituents selected from Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2,
c) pynidyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
d) pyridazinyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
e) pyrimidinyl, unsubstituted or substituted with one, two or three substituents selected from Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
f) imidazolidinyl, unsubstituted or substituted with one, two or three substituents selected from oxo, Xxe2x80x2, Yxe2x80x2, and Zxe2x80x2,
g) 1,3-diazobicyclo[3.3.0]octan-2-onyl,
h) 1,3-diazobicyclo[4.3.0]nonan-2-onyl,
i) NH2,
j) NHR8,
k) NHC1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R8, R9, and R10,
l) NR8R9,
m) NHC(xe2x95x90O)R8,
n) NR8C(xe2x95x90O)R9,
o) NR8C(xe2x95x90O)NHR9,
p) NR8C(xe2x95x90O)NR9R10,
q) NHSO2R8, or
r) NR8SO2R9.
Preferred compounds of the present invention include those of Formula If: 
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein A is phenyl, naphthyl, pyridyl, pyrimidinyl, thienyl, or thiazolyl, and all other substituents are as defined above.
The compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, crystal form or individual diastereomer thereof is selected from the group consisting of:
2-[(S)-1-Phenylethylamino]-4-[5-methylbenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[6-methylbenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[6-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N,N-(dimethyl)-aminobenzimidazol-1-yl]-pyrimidine;
2-((S)-1-(3-nitro-phenyl)ethylamino)-4-[5-methyl-benzimidazol-1-yl]pyrimidine;
2-((S)-1-(3-nitro-phenyl)ethylamino)-4-[6-methyl-benzimidazol-1-yl]pyrimidine;
2-((R)-1-(3-nitro-phenyl)ethylamino)-4-[5-methyl-benzimidazol-1-yl]pyrimidine;
2-((R)-1-(3-nitro-phenyl)ethylamino)-4-[6-methyl-benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-azabenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[6-azabenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N-((morpholin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N-((piperazin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N-(2-aminoethyl)-aminobenzimidazol-1-yl]-pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N-((pyrrolidin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N-(((R)-piperidin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]octan-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]octan-2one-3-yl)-benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(1,3-diazobicyclo[4.3.0]nonan-2-one-3-yl)-benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]4-[5-N-(N-methylcarbamoyl)-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N-(N-ethylcarbamoyl)-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N-(N-propylcarbamoyl)-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-N-(N-((1-methyl)ethylcarbamoyl)aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(tetrazol-1-yl)-benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-N-((pyrrolidin-2-yl)methyl)aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-N-((pyrrolidin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]octan-2-one-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]octan-2-one-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]octan-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]4-[5-( 1,3-diazobicyclo[3.3.0]octan-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-phenylbenzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(thiazol-2-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(furan-2-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[benzimidazol-1-yl]-6-(2-methyl-phenyl)pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-2-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(thiophen-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyrimidin-5-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(4-methoxyphenyl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(3-chlorophenyl)-benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(3-methoxyphenyl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(4-(pyrrol-1-yl)phenyl)benzimidazol-1-yl]-pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(4-methylphenyl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyrimidin-2-yl)benzimidazol-1-yl]-pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(3-methylphenyl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(thiophen-3-yl-carbonyl)benzimidazol-1-yl]-pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyrimidin-5-yl)benzimidazol-1-yl]-pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyrimidin-5-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(4-pyridyl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(3-methoxypyridazin-6-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)- l-Phenylethylamino]-4-[5-(3-chloropyrimidine-6-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(6-methylpyridazin-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(3xe2x80x94N,N-dimethylaminopyridazin-6-yl)-benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]-pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]4-[5-(pyridin-4-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-y1]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(3xe2x80x94N,N-dimethylpyridazin-6-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(3-N,N-dimethylpyridazin-6-yl)benzimidazol-1-yl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyridin4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(3-N,N-dimethylpyridazin-6-yl)benzimidazol-1-yl]6-[2-methylphenyl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;
2-[(S)-1-Phenylethylamino]-4-[5-(3-N,N-dimethylpyridazin-6-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;
2-[(S)-1-(3-Nitromethylphenyl)ethylamino]-4-[5-(pyridin4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;
2-[(S)-1-(3-Trifluorophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;
2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;
2-[(S)-1-(3-Nitromethylphenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;
2-[(S)-1-(3-Trifluorophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine; and
2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine.
The preferred compounds of the present invention include the compounds of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, crystal form, and individual diastereomers thereof, wherein X5 is CRa and X6 is N, and Ra is defined as H or C1-C6-alkyl, and preferably H.
The preferred compounds of the present invention include the compounds of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, crystal form, and individual diastereomers thereof, wherein R1 and R2 independently are: H, R11, NH2, NHR11, orNR11R12.
The preferred compounds of the present invention include the compounds of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, crystal form, and individual diastereomers thereof, wherein xe2x80x94X1xe2x80x94X2xe2x80x94X3xe2x80x94X4xe2x80x94 is: xe2x80x94CR6xe2x95x90CR6xe2x80x94CR6axe2x95x90CR6xe2x80x94, xe2x80x94CR6axe2x95x90CR6xe2x80x94CR6xe2x95x90CR6xe2x80x94, xe2x80x94CR6xe2x95x90Nxe2x80x94CR6xe2x95x90CR6xe2x80x94, or xe2x80x94CR6xe2x95x90CR6xe2x80x94Nxe2x95x90CR6xe2x80x94.
The preferred compounds of the present invention include the compounds of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, crystal form, and individual diastereomers thereof, wherein R6 and R6a are independently: H; halo( Br, Cl, I, or F); R11; OR11; C1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11, R12, and R13; NH2; NHR11; NHC1-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R11, R12, and R13; NR11R12; NHC(xe2x95x90O)R11; NR11C(xe2x95x90O)R12; NR11C(xe2x95x90O)NHR12; NR11C(xe2x95x90O)NR12R13; NHSO2R11; NR11SO2R12; or R6 and R6a when on adjacent carbons can be joined to form a 5- or 6-membered ring having the following bridging atoms, when read from right to left, or left to right: xe2x80x94Nxe2x95x90CHNHxe2x80x94, xe2x80x94NHCHxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90CHNR9xe2x80x94, xe2x80x94NR9CHxe2x95x90Nxe2x80x94, 
The preferred compounds of the present invention include the is compounds of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, crystal form, and individual diastereomers thereof, wherein A is: phenyl, naphthyl, and pyridyl.
The independent syntheses of the diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
As appreciated by those of skill in the art, halo or halogen as used herein is intended to include chloro, fluoro, bromo and iodo. Similarly, C1-6, as in C1-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, such that C1-6 alkyl specifically includes methyl, ethyl, propyl, butyl, pentyl, and hexyl. Likewise, C0, as in C0alkyl is defined to identify the presence of a direct covalent bond. The term xe2x80x9cheterocyclylxe2x80x9d as used herein is intended to include the following groups: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, imidazolidinyl, imidazolidonyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, purinyl, pteridinyl, phthalazinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, benzopiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, 1,3-diazobicyclo[3.3.0]octan-2-onyl, 1,3-diazobicyclo[3.3.0]octanyl, 1,3-diazobicyclo[4.3.0]nonan-2-onyl and N-oxides thereof.
The compounds of Formula I of the present invention inhibit protein tyrosine kinases, especially Src-family kinases such as Lck, Fyn(B), Fyn(T), Lyn, Src, Yes, Hck, Fgr and Blk, and are thus useful in the treatment, including prevention and therapy, of protein tyrosine kinase-associated disorders such as immunologic disorders. xe2x80x9cProtein tyrosine kinase-associated disordersxe2x80x9d are those disorders which result from aberrant tyrosine kinase activity, and/or which are alleviated by the inhibition of one or more of these enzymes. For example, Lck inhibitors are of value in the treatment of a number of such disorders (for example, the treatment of autoimmune diseases), as Lck inhibition blocks T cell activation. The treatment of T cell mediated diseases, including inhibition of T cell activation and proliferation, is a preferred embodiment of the present invention. Compounds of the present invention which selectively block T cell activation and proliferation are preferred. Also, compounds of the present invention which may block the activation of endothelial cell protein tyrosine kinase by oxidative stress, thereby limiting surface expression of adhesion molecules that induce neutrophil binding, and which can inhibit protein tyrosine kinase necessary for neutrophil activation would be useful, for example, in the treatment of ischemia and reperfusion injury.
The present invention also provides methods for the treatment of protein tyrosine kinase-associated disorders, comprising the step of administering to a subject in need thereof at least one compound of the formula I in an amount effective therefor. Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
Use of the compound(s) of Formula I of the present invention in treating protein tyrosine kinase-associated disorders is exemplified by, but is not limited to, treating a range of disorders such as: transplant (such as organ transplant, acute transplant or heterograft or homograft (such as is employed in burn treatment)) rejection; protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes; transplantation tolerance induction; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; inflammatory bowel disease, including ulcerative colitis and Crohn""s disease; lupus (systemic lupus erythematosis); graft vs. host diseases; T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); Type 1 diabetes; psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto""s thyroiditis; Sjogren""s syndrome; Autoimmune Hyperthyroidism, such as Graves"" Disease; Addison""s disease (autoimmune disease of the adrenal glands); Autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; other autoimmune diseases; cancers where Lck or other Src-family kinases such as Src are activated or overexpressed, such as colon carcinoma and thymoma, or cancers where Src-family kinase activity facilitates tumor growth or survival; glomerulonephritis, serum sickness; uticaria; allergic diseases such as respiratory allergies (asthma, hayfever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute inflammatory responses (such as acute respiratory distress syndrome and ishchemia/reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet""s disease; Pustulosis palmoplanteris; Pyoderma gangrenum; Sezary""s syndrome; atopic dermatitis; systemic schlerosis; and morphea. The present invention also provides for a method for treating the aforementioned disorders such as atopic dermatitis by administration of a therapeutically effective amount of a compound of Formula I of the present invention, which is an inhibitor of protein tyrosine kinase, to a patient in need of such treatment.
Src-family kinases other than Lck, such as Hck and Fgr, are important in the Fc gamma receptor induced respiratory burst of neutrophils as well as the Fc gamma receptor responses of monocytes and macrophages. The compounds of the present invention may inhibit the Fc gamma induced respiratory burst response in neutrophils, and may also inhibit the Fc gamma dependent production of TNF alpha. The ability to inhibit Fc gamma receptor dependent neutrophil, monocyte and macrophage responses would result in additional anti-inflammatory activity for the present compounds in addition to their effects on T cells. This activity would be especially of value, for example, in the treatment of inflammatory diseases, such as arthritis or inflammatory bowel disease. The present compounds may also be of value for the treatment of autoimmune glomerulonephritis and other instances of glomerulonephritis induced by deposition of immune complexes in the kidney that trigger Fc gamma receptor responses and which can lead to kidney damage.
In addition, certain Src family kinases, such as Lyn and Fyn(B), may be important in the Fc epsilon receptor induced degranulation of mast cells and basophils that plays an important role in asthma, allergic rhinitis, and other allergic disease. Fc epsilon receptors are stimulated by IgE-antigen complexes. The compounds of the present invention may inhibit the Fc epsilon induced degranulation responses. The ability to inhibit Fc epsilon receptor dependent mast cell and basophil responses may result in additional anti-inflammatory activity for the present compounds beyond their effect on T cells.
The combined activity of the present compounds towards monocytes, macrophages, T cells, etc. may prove to be a valuable tool in the treatment of any of the aforementioned disorders.
In a particular embodiment, the compounds of formula I of the present invention are useful for the treatment of the aforementioned exemplary disorders irrespective of their etiology, for example, for the treatment of transplant rejection, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, lupus, graft v. host disease, T-cell mediated hypersensitivity disease, psoriasis, Hashimoto""s thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic disease such as allergic rhinitis, asthma, ischemic or reperfusion injury, or atopic dermatitis whether or not associated with PTK.
The present invention also provides pharmaceutical compositions comprising at least one of the compounds of the formula I capable of treating a protein tyrosine kinase-associated disorder in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The compounds of the formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
Diseases and conditions associated with inflammation and infection can be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
The subjects treated in the above methods, in whom which protein tyrosine kinase inhibition is desired, are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The term xe2x80x9ccompositionxe2x80x9d as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms xe2x80x9cadministration ofxe2x80x9d and or xe2x80x9cadministering axe2x80x9d compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
Examples of other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-xcex1inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.
When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise deterrnined by one of ordinary skill in the art.
In the treatment or prevention of conditions which require protein tyrosine kinase inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The following assays can be employed in ascertaining the degree of activity of a compound as a protein tyrosine kinase inhibitor. Compounds described herein have been tested in one or more of the assays, and have shown activity. Representative compounds of the invention were tested and found to exhibit IC50 values of at least  less than 10 xcexcM in any one of the described assays, thereby demonstrating and confirming the utility of the compounds of the invention as protein tyrosine kinase inhibitors and in the prophylaxis and treatment of immune diseases, hyperproliferative disorders, etc.
This assays measures the ability of compounds to block intracellular ZAP-70 kinase activation after stimulation of Jurkat T cells with anti-T cell receptor antibodies.
Step 1: Preparation of Jurkat Cells
Wash confluent Jurkat cells 2 times in serum-free RPMI (Gibco). Resuspend cells at 1.1xc3x97106 cells/ml in serum free-RPMI, keep on ice.
Step 2: Dilute Compounds
Titer test compounds in DMSO, prepare 110xc3x97 concentrated solutions.
Step 3: Prepare Anti Vb8 Stock
Dilute anti-Vb8 (Pharmingen) to 917 ng/ml in Tris buffered saline.
Step 4: Run Cell Assay
For each test compound, place 12 V-bottom polypropylene PCR tubes in a thermal cycler (MJ Research) set at 0xc2x0 C. Run no more than 4 compounds at a time. Also run 2 samples which receive just RPMI instead of anti-Vb8. These controls should be harvested at time=0 and time=2.5 minutes. To test for nonspecific interference with the assay, run cells plus anti-Vb8 for each drug tested and later, after these cells are lysed, add I ml of the test compound dilutions. Add 100 ml of Jurkat cells to each tube. Add 1 ml of test compounds diluted in DMSO. Add 9 ml of anti-Vb8 and mix. Incubate 5 min at 0xc2x0 C. Add 2x Lysis Buffer to time=0 and no anti-Vb8 control. Set thermal cycler to 37xc2x0 C. At time xe2x95x902.5 minutes, add 110 ml of 2xc3x97 Lysis Buffer to each well. Freeze samples in dry ice ethanol. They can be stored overnight at xe2x88x9280xc2x0 C., or you can continue with the assay.
Step5: Run ZAP-70 Kinase Assay
Thaw cell lysates. Prepare 2xc3x97 Kinase Reaction Buffer. Mix lysates well and put duplicate 25 ml aliquots into black U bottom plates (Falcon). Add 25 ml of 2xc3x97 kinase mix. Seal plate and incubate 30 min at 30xc2x0. Add 50 ml 2xc3x97 Quench solution. Leave plates in dark for 1 hour. Measure time-resolved fluorescent energy transfer in a Discovery plate reader (Packard).
Step 1: IL2 Secretion from Antigen-stimulated T Cells
Mix 30,000 Jurkat-mart#22 T cells with 30,000 T2 antigen presenting cells in 100 xcexcl of RPMI medium containing 10% fetal calf serum in 96 well flat-bottom tissue culture plates (Falcon). Add 1 xcexcl of compound titered in DMSO. Add 99 xcexcl of 1 xcexcM of M9-2 peptide [Ala-Ala-Gly-Ile-Gly-Ile-Leu-Thr-Val]. Incubate overnight at 37xc2x0 C. in a 5% CO2 incubator. Collect culture supernatants.
Step 2: Measurement of IL2 in Culture Supernatant
Coat Immulon2 plates (Dynatech) with 50 xcexcl anti-human IL-2 (R andD) at 4 xcexcg/ml in PBS/0.05% azide. Incubate overnight at 4xc2x0 C. Block wells for at least 1 hour at room temperature with Block Buffer: Tris buffered saline (TBS)/1% BSA/0.05% azide. Wash wells 3 times with Wash Buffer: TBS/0.01% Tween 20. Add 50 xcexcl of culture supernatants, or IL2 standards, to the microtiter wells. Incubate 1 hour at room temperature. Wash plate 3 times with Wash Buffer. Add 75 xcexcl of anti-human IL-2-Biotin (RandD) at 450 ng/ml in Block Buffer. Incubate 1 hour at room temperature. Wash wells 3 times with Wash Buffer. Add 100 xcexcl of 1 xcexcg/ml europium-conjugated streptavidin (Wallac). Incubate 20 minutes at room temperature. Wash plate 3 times with Wash Buffer. Add 150 xcexcl Enhancement solution (Wallac) Incubate 30 at least minutes at room temperature. Measure time resolved europium fluorescence on a Victor2 plate reader (Wallac).
Materials:
N-LCB-EQEDEPEGDYEEVLE-NH2 (peptide substrate for Src family tyrosine kinases, Lck, Fyn(T), Fyn(B), Lyn, Src, Blk, Hck, Fgr, and Yes; LCB=aminohexanoylbiotin), N-LCB-EQEDEPEGIYGVLF-NH2 (peptide substrate for ZAP-70, Syk, and Csk) were synthesized using an Applied Biosystem""s 433A peptide synthesizer using FastMOC(trademark) chemistry. All the Src family (Lck, Fyn(T), Fyn(B), Lyn, Src, Blk, Hck, Fgr, and Yes) as well as ZAP-70, Syk and Csk tyrosine kinases were expressed and purified using standard techniques known in the art. Streptavidin-XL665 (Streptavidin labeled with crosslinked allophycocyanin) was purchased from CISbio (France). Eu(K)-PY20 (Anti-phosphotyrosine antibody, PY20, labeled with Europium Cryptate) was using procedures described in: xe2x80x9cUse Of A Phosphotyrosine-Antibody pair As A General Detection Method In Homogeneous Time Resolved Fluorescence: Application To Human Immunodeficency Viral Proteasexe2x80x9d Cummings, R. T., McGovern, H. M., Zheng, S., Park, Y. W., and Hermes, J. D. Analytical Biochemistry, Vol 269, 79-93 (1999); and xe2x80x9cHomogeneous Proximity Tyrosine Kinase Assays: Scintialltion Proximity Assay Versus Homogeneous Time Resolved Fluorescencexe2x80x9d Park, Y. W., Cummings, R. T., Wu, L., Zheng, S., Cameron, P. M., Woods, A., Zaller, D., Marcy, A. I., and Hermes, J. D. Analytical Biochemistry, Vol 269, 94-104 (1999). Anti-phosphotyrosine antibody PY20 and Europium Cryptate were purchased from Transduction Laboratories (Lexington, Ky.) and CISbio (France), respectively.
General Assay Protocol
Standard assay conditions were 50 xcexcL kinase reaction consisting of 0.75 xcexcM N-biotinyl peptide substrate and 10 xcexcM ATP in assay buffer (50 mM Hepes, pH 7.0, 10 mM MgCl2, 0.1% BSA, and 1 mM DTT). The kinase reaction was initiated by adding enzyme (2-20 pM) in a black MicroFluor 96-well plate (Dynatech, Chantilly, Va.). After a 40-minute incubation at room temperature, 50 xcexcL of HTRF reagent mixture (420 nM streptavidin-XL665 and 2.0 nM Eu(K)-PY20) in quench buffer (50 mM Hepes, 30 mM EDTA, 0.1% BSA, 0.1% Triton X-100, 0.2 M KF, and pH 7.25) was added to the reaction mixture. The quenched reaction was incubated for 30 min. at room temperature and then read in Discovery (Packard, Meriden, Conn.).
Detailed Assay Procedure
General assay conditions: 0.75 xcexcM substrate (biotinylated peptide), 10 xcexcM ATP, 2-20 pM kinase, 210 nM SA-XL665 (Streptavidin labeled with crosslinked allophycocyanin), 1.0 nM Ab-K (anti-pTyr antibody, PY20, labeled with Europium Cryptate).
Assay Buffer: 50 mM HEPES, 10 mM MgCl2, 1 mg/ml BSA, 1 mM DTT (fresh), 10 xcexcM ATP (fresh), pH 7.0
Quench Buffer: 50 mM HEPES, 30 mM EDTA, 0.2 M KF, 1 mg/ml BSA, 0.1% Triton X-100, pH 7.25
Preparation:
1. 1.88 xcexcM substrate2 from 1 mM stock (in 100% DMSO).
2. 5.4 pM enzyme2 from 500 nM stock (in 50% glycerol).
3. 420 nM (based on 4 biotin binding sites) SA-XL665 2.0 nM, Ab-K3 in quench buffer.
1For 100 xcexcL kinase/200 xcexcL total assay, all the reagents should be doubled. 
2diluted with assay buffer 
3diluted with quench buffer 
Assay procedure:
1. Add 20 xcexcl of 1.88 xcexcM substrate in a round-bottom 96-well black plate (Dynatech or Costar).
2. Add 2 xcexcl of inhibitor (or DMSO for controls).
3. Add 28 xcexcl of 5.4 pM enzyme.
4. Incubate for 40 min. at RT.
5. Quench the kinase reaction by adding 50 xcexcl of quench buffer with 420 nM XL and 2.0 nM Eu-PY20.
6. Incubate 30 min. at RT.
7. Read in Packard""s Discovery.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made from known procedures or as illustrated. 
The preparation of substituted benzimidazoles such as 1-2 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 1. Benzimidazoles of structure 1-2 can be obtained commercially or can be synthesized by reacting a suitably substituted ortho-diaminobenzene 1-1 with formic acid, formamidine, triazine, dimethylformamide, dimethylformamide dialkylacetal, chloromethylenedimethylammonium chloride, trialkylorthoformate, (dimethylaminomethylene)-aminomethylenedi methylammonium chloride (Gold""s reagent) or the like. The ortho-diaminobenzene 1-1 can be obtained commercially or can be prepared in a variety of ways from commercial materials. The benzimidazole can be further substituted via aromatic substitution or modification of the substituents prior to or after incorporation onto the pyrimidine ring of the instant invention. The substituents Y and Z may include but are not limited to alkyl, aryl, heteroaryl, nitro, amino, substituted amino, disubstituted amino, hydroxy, alkoxy, aryloxy, chloro, bromo, iodo, fluoro, azido, cyano, thio, alkylthio, arylthio, carboxy, acyl, alkoxycarbonyl and alkylaminocarbonyl groups. Additionally, substituents Y and Z may form a third ring fused to the benzimidazole. Additionally, other heterocycles such as unsubstituted and substituted indoles, azaindoles, azabenzimidazoles, benzotriazoles, purines or the like can also be used. 
The preparation of 2,4-dichloropyrimidines such as 2-3 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 2. Pyrimidines of structure 2-3 can be obtained commercially or can be synthesized by condensation of a xcex2-keto-ester, xcex2-keto-acid, xcex2-keto-nitrile, xcex2-aldehydo-ester, xcex2-aldehydo-acid, xcex2-aldehydo-nitrile, xcex2-diester, xcex2-ester-nitrile or the like with urea in a suitable solvent such as methanol, ethanol isopropanol or the like in the presence of a base such as a sodium or potassium alkoxide to give a substituted uracil. Other methods of pyrimidine ring formation can be used (see Katritzky, A. R. and Rees, C. W. xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d Pergamon Press pp. 106-142 (1984)). The uracil can be chlorinated at the 2- and 4-positions by treatment with phosphoryl chloride, phosphorous pentachloride, phosphorous trichloride or mixtures thereof, or with chloromethylenedimethylammonium chloride added separately or prepared in situ by treatment of dimethylformamide with thionyl chloride, phosgene or the like in methylene chloride, chloroform, tetrahydrofuran, dioxane, ether or other suitable solvent. Alternately, other halides such as bromine or iodine can be incorporated in place of chlorine. 
The preparation of some 2-amino-4-chloropyrimidines such as 3-3 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 3. 2-Amino-4-chloropyrimidines 3-3 can be obtained commercially or can be synthesized by treatment of a 2,4-dichloropyrimidine 3-1 with a primary or secondary amine 3-2 in ethanol, methanol, isopropanol, tetrahydrofuran, ether, dioxane, dichloromethane, chloroform or other suitable solvent with or without the presence of a tertiary amine base. The regioisomeric 2-amino-4-chloropyrimidines are also obtained and can be used as intermediates in the instant invention. 
The preparation of some 2-amino-4-chloropyrimidines such as 4-4 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 4. 2-Amino-4-chloropyrimidines 4-4 can be obtained commercially or can be synthesized by treatment of a xcex2-keto-ester, xcex2-keto-acid, xcex2-keto-nitrile, xcex2-aldehydo-ester, xcex2-aldehydo-acid, xcex2-aldehydo-nitrile, xcex2-diester, xcex2-ester-nitrile or the like with with an N-alkylguanidine 4-2 to give 2-amino-4-hydroxypyrimidine 4-3 generally in an alcoholic solvent such as methanol, ethanol, isopropanol in the presence of a strong base such as sodium methoxide, sodium ethoxide or the like. N-alkylguanidine 4-2 can be prepared according to the procedure of Kim et al (Tetrahedron Letters, 1988, 29 , 3183 and references cited therein). The 2-amino-4-hydroxypyrimidine 4-3 can be chlorinated by treatment with phosphoryl chloride, phosphorous pentachloride, phosphorous trichloride or mixtures thereof, or with chloromethylenedimethylammonium chloride added separately or prepared in situ by treatment of dimethylformamide with thionyl chloride, phosgene or the like in methylene chloride, chloroform, tetrahydrofuran, ether or other suitable solvent. Alternately, other halides such as bromine or iodine can be incorporated in place of chlorine. 
The preparation of some 2-alkylthio-4-chloropyrimidines such as 5-4 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 5. 2-Alkylthio-4-chloropyrimidines 5-4 can be obtained commercially or can be synthesized by treatment of a xcex2-keto-ester, xcex2-keto-acid, xcex2-keto-nitrile, xcex2-aldehydo-ester, xcex2-aldehydo-acid, xcex2-aldehydo-nitrile, xcex2-diester, xcex2-ester-nitrile or the like in an alcoholic solvent such as methanol, ethanol or the like with an S-alkylthiopseudourea to give 2-alkylthio-4-hydroxy pyrimidine 5-3. The 2-alkylthio4-hydroxy pyrimidine 5-3 can be chlorinated by treatment with phosphoryl chloride, phosphorous pentachloride, phosphorous trichloride or mixtures thereof, or with chloromethylenedimethylammonium chloride added separately or prepared in situ by treatment of dimethylformamide with thionyl chloride, phosgene or the like in methylene chloride, chloroform, tetrahydrofuran, ether or other suitable solvent. Alternately, other halides such as bromine or iodine can be incorporated in place of chlorine. 
The preparation of some 2-alkylamino-4-[benzimidazol-1-yl]pyrimidines such as 6-3 within the scope of the instant invention is detailed in Scheme 6. A benzimidazole 6-1 is condensed with a 2-amino-4-chloropyrimidine 6-2 in a suitable solvent such as dimethylformamide, dimethylsulfoxide, toluene, tetrahydrofuran, xylene, 1-methyl-2-pyrrolidinone, isopropanol or the like at or above room temperature. The benzimidazole 6-1 can first be deprotonated by addition of a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide or the like prior to condensation with 2-amino-4-chloropyrimidine 6-2. 
The preparation of some 2-alkylamino-4-[benzimidazol-1-yl]pyrimidines such as 7-6 within the scope of the instant invention is detailed in Scheme 7. A benzimidazole 7-1 is condensed with a 2-alkylthio-4-chloropyrimidine 7-2 in a suitable solvent such as dimethylformamide, dimethylsulfoxide, toluene, tetrahydrofuran, xylene, 1-methyl-2-pyrrolidinone, isopropanol or the like at or above room temperature to afford a 2-alkylthio-4-[benzimidazol-1-yl]pyrimidine 7-3. The benzimidazole 7-1 can first be deprotonated by addition of a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide or the like prior to condensation with 2-alkylthio4-chloropyrimidine7-2. The 2-alkylthio-group of 7-3 can be displaced by an alkyl amine 7-5 or preferably, the alkylthio group of 7-3 can first be oxidized to the corresponding sulfoxide or sulfone using hydrogen peroxide, sodium periodate, sodium chlorite, sodium hypochlorite, peracids, Oxone(copyright) or the like and then displaced with an alkylamine 7-5 to give 2-alkylamino-4-[benzimidazol-1-yl]pyrimidines such as 7-6. 
The preparation of some 2-alkylamino-4-[benzimidazol-1-yl]-6-arylpyrimidines such as 8-9 within the scope of the instant invention is detailed in Scheme 8. A 2,4,6-trichloropyrimidine 8-1 is condensed with an alkylamine 8-2 in ethanol, methanol, isopropanol, tetrahydrofuran, ether, methylene chloride, chloroform or other suitable solvent with or without the presence of a tertiary amine base to afford a 2-alkylamino-4,6-dichloropyrimidine 8-3. A benzimidazole 8-5 is condensed with 2-alkylamino-4,6-dichloropyrimidine 8-3 in a suitable solvent such as dimethylformamide, dimethylsulfoxide, toluene, tetrahydrofuran, xylene, 1-methyl-2-pyrrolidinone, isopropanol or the like at or above room temperature to afford the 2-alkylamino-4-[benzimidazol-1-yl]-6-chloropyrimidine 8-6. The benzimidazole 8-5 can first be deprotonated by addition of a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide or the like prior to condensation with 2-alkylamino-4,6-dichloropyrimidine 8-3. The 2-alkylamino4-benzimidazol-1-yl-6-chloropyrimidine 8-6 is arylated via a palladium mediated coupling with an arylboronic acid or an aryltrialkyltin reagent to give 2-alkylamino-4-[benzimidazol-1-yl]-6-arylpyrimidine such as 8-9. 
The preparation of 2-alkylamino-4-[acylamino-benzimidazol-1-yl]pyrimidines such as 9-3 within the scope of the instant invention is detailed in Scheme 9. A 2-aminoalkyl-4-[aminobenzimidazol-1-yl]pyrimidine 9-1 is treated with an acid chloride 9-2 in pyridine or in a non-protic solvent such as methylene chloride, chloroform, tetrahydrofuran, toluene or the like in the presence of a tertiary amine base to give 2-alkylamino-4-[acylamino-benzimidazol-1-yl]pyrimidines such as 9-3. In place of the acid chloride one can use another acid halide, or other acylating agent such as acid anhydrides, esters, isocyanates, chloroformates, alkylsulfonylchlorides, arylsulfonylchlorides, or an acid with a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1,3-dicyclohexylcarbodiimide or the like. Alternatively, the acylation can be carried out on a 1-N-protected-amino-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the acylamino-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[alkylamino-benzimidazol-1-yl]pyrimidines such as 10-3 within the scope of the instant invention is detailed in Scheme 10. A 2-aminoalkyl-4-[aminobenzimidazol-1-yl]pyrimidine 10-1 is treated with an aldehyde or ketone 10-2 in a suitable solvent such as dichloromethane, dichloroethane, tetrahydrofuran methanol, ethanol, acetic acid or the like to which is added a hydride source such as sodium borohydride, sodium cyanoborohydride, borane, sodium triacetoxyborohydride or the like to give 2-alkylamino-4-[alkylamino-benzimidazol-1-yl]pyrimidines such as 10-3. An alternative method of preparation of 2-alkylamino-4-[alkylamino-benzimidazol-1-yl]pyrimidines such as 10-3 is by the reduction of the amide group of a 2-alkylamino-4-[acylamino-benzimidazol-1-yl]pyrimidine using borane, lithium aluminum hydride or the like. An alternative method of preparation of 2-alkylamino4-[alkylamino-benzimidazol-1-yl]pyrimidines such as 10-3 is by alkylation of a 2-aminoalkyl-4-[aminobenzimidazol-1-yl]pyrimidine 10-1 with an alkylhalide or alkylsulfonate. Alternatively, the alkylation can be carried out on a 1-N-protected-amino-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the alkylamino-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[imidazolidin-2-one-1-yl-benzimidazol-1-yl]pyrimidines such as 11-3 within the scope of the instant invention is detailed in Scheme 11. A 2-alkylamino-4-[(aminoalkyl)amino-benzimidazol-1-yl]pyrimidine 11-1 is treated with carbonyldiimidazole 11-2 or phosgene, triphosgene, 4-nitrophenylchloroformate or the like in a suitable solvent such as dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, dimethylformamide or the like with or without the presence of a tertiary amine base such as triethylamine, diisopropylethylamine, 4-dimthylaminopyridine or the like to afford the 2-alkylamino-4-[imidazolidin-2-one-1-yl-benzimidazol-1-yl]pyrimidine 11-3. Alternatively, the cyclization can be carried out on a 1-N-protected-(aminoalkyl)amino-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the imidazolidin-2-one-1-yl -benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[arylaminobenzimidazol-1-yl]pyrimidines such as 12-3 within the scope of the instant invention is detailed in Scheme 12. A 2-aminoalkyl-4-[aminobenzimidazol-1-yl]pyrimidine 12-1 is treated with a triarylbismuth 12-2 in the presence of stoichiometric copper(II)acetate or with a triarylbismuth diacetate or other pentavalent organobismuth in the presence of catalytic copper(II)acetate. An alternate procedure involves reaction of a 2-aminoalkyl-4-[aminobenzimidazol-1-yl]pyrimidine 12-1 with an aryl halide in the presence of a palladium catalyst and strong base according to the procedure of Buchwald et al (J. Am. Chem. Soc. 1997, 119, 8451). Alternatively, the arylation can be carried out on a 1-N-protected-amino-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the arylamino-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[substituted-benzimidazol-1-yl]pyrimidine such as 13-4 within the scope of the instant invention is detailed in Scheme 13. A 2-aminoalkyl-4-[aminobenzimidazol-1-yl]pyrimidine 13-1 is treated with an acid such as acetic acid, tetrafluoroboric acid, hydrochloric acid or the like followed by isoamylnitrite, sodium nitrite, nitrous acid or the like to afford the diazonium salt 13-3. The 2-alkylamino-4-[diazonium-benzimidazol-1-yl]pyrimidines 13-3 can then be treated with cuprous chloride or cuprous bromide or sodium iodide or potassium iodide or the like to afford the corresponding 2-alkylamino-4-[halo-benzimidazol-1-yl]pyrimidine. The 2-alkylamino-4-[diazonium-benzimidazol-1-yl]pyrimidines 13-3 can also be treated with cuprous cyanide to afford the corresponding 2-alkylamino-4-[cyano-benzimidazol-1-yl]pyrimidine. The 2-alkylamino-4-[diazonium-benzimidazol-1-yl]pyrimidines 13-3 can also be treated with sodium azide to afford the corresponding 2-alkylamino-4-[azido-benzimidazol-1-yl]pyrimidine. The 2-alkylamino-4-[diazonium-benzimidazol-1-yl]pyrimidines 12-3 can also be treated with an olefin, a vinylstannane, an arylboronic acid, an arylstannane or the like in the presence of a palladium catalyst to afford the corresponding 2-alkylamino-4-[(aryl or vinyl)-benzimidazol-1-yl]pyrimidine. The stannane couplings can also be done in the presence of carbon monoxide to afford the carbonyl insertion products.
Alternatively, the diazotization and subsequent substitution reaction can be carried out on a 1-N-protected-amino-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the substituted-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[triazol-1-yl-benzimidazol-1-yl]pyrimidine such as 14-3 within the scope of the instant invention is detailed in Scheme 14. A 2-alkylamino-4-[azido-benzimidazol-1-yl]pyrimidine can be treated with an alkyne or aminoacrylate with heating to afford the 2-alkylamino-4-[triazolyl-benzimidazol-1-yl]pyrimidine. When the alkyne used is tributylethynylstannane, the resulting tributylstannyltriazole (R5=bu3Sn) can be used for further palladium catalysed couplings with aryl or olefinic groups or can be proto-destannylated. Alternatively, the triazole formation can be carried out on a 1-N-protected-azido-benzimidazole. The protecting group for the benzirnidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the triazol-1-yl-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[tetrazol-1-yl-benzimidazol-1--yl]pyrimidines such as 15-3 within the scope of the instant invention is detailed in Scheme 15. A 2-alkylamino-4-[amino-benzimidazol-1-yl]pyrimidine 15-1 is treated with a trialkyl orthoformate 15-2 followed by treatment with sodium azide to give the 2-alkylamino-4-[tetrazolyl-benzimidazol-1-yl]pyrimidine 15-3. Alternatively, the tetrazole formation can be carried out on a 1-N-protected-amino-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the tetrazol-1-yl-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[tetrazol-5-yl-benzimidazol-1-yl]pyrimidines such as 16-3 within the scope of the instant invention is detailed in Scheme 16. A 2-alkylamino-4-[cyano-benzimidazol-1-yl]pyrimidine 16-1 is treated with trimethylsilyl azide 16-2 or trialkyltin azide or sodium azide or the like at or above room temperature to give the 2-alkylamino-4-[tetrazol-5-yl-benzimidazol-1-yl]pyrimidine 16-3. Alternatively, the tetrazole formation can be carried out on a 1-N-protected-cyano-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the tetrazol-5-yl-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[(alkylaminocarbonyl)-benzimidazol-1-yl]pyrimidines such as 17-3 within the scope of the instant invention is detailed in Scheme 17. A 2-alkylamino-4-[carboxy-benzimidazol-1-yl]pyrimidine 17-1 is treated with an amine 17-2 in the presence of a tertiary amine such as N-methylmorpholine, triethylamine or the like and a coupling reagent such as 1,3-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or the like to give the 2-alkylamino-4-[(alkylaminocarbonyl)-benzimidazol-1-yl]pyrimidine 17-3. Alternatively, the amide formation can be carried out on a 1-N-protected-carboxy-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the (alkylaminocarbonyl)-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylarnino-4-[alkyl (or aryl)carbonyl-benzimidazol-1-yl]pyrimidines such as 18-3 within the scope of the instant invention is detailed in Scheme 18. A 2-alkylamino-4-[(N-methy1-N-methoxyamino)carbonyl-benzimidazol-1-yl]pyrimidine 18-1 is treated with an organomagnesium halide 18-2 or organolithium or the like in a suitable solvent such as dichloromethane, ethe,r tetrahydrofuran, dichloroethane, dioxane or the like to give the 2-alkylamino-4-[alkyl (or aryl)carbonyl -benzimidazol-1-yl]pyrimidine 18-3. Alternatively, the ketone formation can be carried out on a 1-N-protected-(N-methyl-N-methoxyamino)carbonyl-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the alkyl (or aryl)carbonyl-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of 2-alkylamino-4-[substituted-benzimidazol-1-yl]pyrimidine such as 19-3 within the scope of the instant invention is detailed in Scheme 19. A 2-aminoalkyl-4-[iodobenzimidazol-1-yl]pyrimidine 19-1 or 2-aminoalkyl-4-[bromobenzimidazol-1-yl]pyrimidine or 2-aminoalkyl-4-[chlorobenzimidazol-1-yl]pyrimidine is treated with an olefin, arylstannane, vinylstannane, arylboronic acid, vinylboronic acid or the like in the presence of a palladium catalyst to afford the corresponding 2-alkylamino-4-[(aryl or vinyl)-benzimidazol-1-yl]pyrimidine 19-3. The stannane couplings can also be done in the presence of carbon monoxide to afford carbonyl insertion products. Alternatively, the 2-aminoalkyl-4-[iodobenzimidazol-1-yl]pyrimidine 19-1 or 2-aminoalkyl-4-[bromobenzimidazol-1-yl]pyrimidine or 2-aminoalkyl-4-[chlorobenzimidazol-1-yl]pyrimidine can be treated with hexabutylditin or hexamethylditin in the presence of a palladium catalyst to afford the corresponding 2-aminoalkyl-4-[trialkylstannylbenzimidazol-1-yl]pyrimidine which can also be employed in palladium mediated couplings with arylboronic acids, vinyl boronic acids, arylhalides, vinyl halides or the like. Alternatively, the arylation or vinylation can be carried out on a 1-N-protected-halo (or stannyl)-benzimidazole. The protecting group for the benzimidazole can be, but is not limited to, a trimethylsilylethoxymethyl (SEM) group. After removal of the 1-N-protecting group the substituted-benzimidazole can be incorporated onto the pyrimidine nucleus as outlined in Scheme 6, Scheme 7 or Scheme 8 to give compounds of the instant invention. 
The preparation of some I-phenylethylamines such as 20-4 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 20. 1-phenylethylamines of structure 20-4 can be obtained commercially or can be synthesized by the reduction of an acetophenone to the corresponding alcohol. Activation of the alcohol towards displacement by formation of the methanesulfonate, toluenesulfonate, halhalide or the like followed by substitution with the azide anion affords azido compound 20-3. Reduction of the azide by treatment with triphenylphosphine in aqueous THF or by hydrogenation over a palladium catalyst affords the amine 20-4. Other methods of amine formation can be used (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1276-1277(1992)). 
The preparation of piperidine substituted ethylamines such as 21-7 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 21. The nitrogen of the commercially available 3-piperidinemethanol can be protected with a benzyloxycarbonyl group or other suitable protecting group such as tert-butyloxycarbonyl-, allyloxycarbonyl- or the like to afford 21-2. The hydroxyl group of 21-2 can be oxidized to the corresponding carbonyl group under Swern oxidation conditions. Other methods for oxidizing a primary hydroxy group to an aldehyde can also be used, for example the Dess-Martin periodinane, or with various chromium trioxide-based reagents (see March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 1167-1171 (1992)). Addition of methyl magnesium bromide or methyl lithium can afford the secondary alcohol 21-4. The hydroxyl group of 21-4 can be activated towards displacement by formation of methanesulfonate, toluenesulfonate, halide or the like. Treament of 21-5 with sodium azide in dimethylformamide or other suitable solvent affords azido compound 21-6. Alternatively, 21-4 can be treated with azide ion under Mitsunobu coupling conditions to give azide 21-6 directly. Reduction of the azide to the corresponding amine by treatment of the azide with triphenylphosphine in aqueous THF gives the desired amine 21-7. Alternatively, the azide can be reduced by hydrogenation over a suitable catalyst. Alkylamines substituted with other heterocycles such as, but not limited to, 2-pyrrolidine, 3-pyrrolidine, 2-piperidine, 4-piperidine, piperazine, 2-morpholine, 3-morpholine, 2-thiomorpholine and the corresponding S-oxides, 3-thiomorpholine and the corresponding S-oxides, can also be prepared in like manner. 
The preparation of 2-(piperidin-3-yl)ethylamino-4-[benzimidazol-1-yl]pyrimidines such as 22-3 within the scope of the instant invention is detailed in Scheme 22. Sulfone 22-1 described in Scheme 7 can be reacted with a piperidine-substituted alkylamines such as 22-2 in dimethyformamide, dimethylsulfoxide, toluene, 1-methyl-2-pyrrolidinone, isopropanol or other suitable solvent with or without heating to give the N-benzyloxycarbonyl-protected heterocycle 22-3. Alternatively, the (piperidin-3-yl)ethylamino can be affixed to the pyrimidine ring prior to the benzimidazole as described in Scheme 3, Scheme 6 and Scheme 8. Additionally, other (heterocyclic)alkylamines such as alkylamines substituted with, for example, 2-pyrrolidine, 3-pyrrolidine, 2-piperidine, 4-piperidine, piperazine, 2-morpholine, 3-morpholine, 2-thiomorpholine and the corresponding S-oxides, 3-thiomorpholine and the corresponding S-oxides, can also be used. 
The preparation of 2-(piperidin-3-yl)ethylamino-4-[benzimidazol-1-yl]pyrimidines such as 23-4 within the scope of the instant invention is detailed in Scheme 23. Removal of the benzyloxycarbonyl protecting group of 23-1 via hydrogenolysis using a palladium catalyst or by solvolysis using HBr in acetic acid affords the deprotected compound 23-2 within the scope of the instant invention. Subsequent acylation with an acid chloride 22-3 in pyridine or in a solvent such as methylene chloride, chloroform, tetrahydrofuran, toluene or the like in the presence of a tertiary amine base gives 22-4. In place of the acid chloride one can use another acid halide, or other acylating agent such as acid anhydrides, esters, isocyanates, chloroformates, alkylsulfonyl halides, arylsulfonyl halides or an acid with a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1,3-dicyclohexylcarbodiimide or the like. Alternatively, the acylation can be carried out on the (heterocyclic)alkylamine prior to incorporation onto the pyrimidine ring of the instant invention. 
The preparation of 2-(piperidin-3-yl)ethylamino-4-[benzimidazol-1-yl]pyrimidines such as 24-3 within the scope of the instant invention is detailed in Scheme 24. Treatment of piperidine 24-1 with an alkyl halide, or alkylsulfonate or the like in dichloromethane, dichloroethane, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide acetone or other suitable solvent in the presence of a tertiary amine base such as triethylamine, diisopropylethylamine or the like affords the alkylpiperidine derivative 24-3. Alternatively, 24-1 can be treated with an aldehyde or ketone under reductive alkylation conditions to give the alkylpiperidine derivative 24-3. Alternatively, the alkylation can be carried out on the (heterocyclic)alkylamine prior to incorporation onto the pyrimidine ring of the instant invention. 
The preparation of 2-(N-arylpiperidine)ethylamino-4-[benzimidazol-1-yl]pyrimidines such as 25-3 within the scope of the instant invention is detailed in Scheme 12. A 2-(piperidin-3-yl)ethylamino-4-[benzimidazol-1-yl]pyrimidine 25-1 is treated with a triarylbismuth 25-2 in the presence of stoichiometric copper(II)acetate or with a triarylbismuth diacetate or other pentavalent organobismuth in the presence of catalytic copper(II)acetate to afford 25-3. An alternate procedure involves reaction of a 2-(piperidin-3-yl)ethylamino-4-[benzimidazol-1-yl]pyrimidine 25-1 with an aryl halide in the presence of a palladium catalyst and strong base according to the procedure of Buchwald et al (J. Am. Chem. Soc. 1997, 119, 8451). Alternatively, the arylation can be carried out on the (heterocyclic)alkylamine prior to incorporation onto the pyrimidine ring of the instant invention. 
The preparation of piperazine substituted alkylamines such as 26-7 as intermediates that can be used for the synthesis of compounds within the scope of the instant invention is detailed in Scheme 26. The nitrogens of the commercially available piperazine-2-carboxylic acid can be sequentially protected with a tert-butyloxycarbonyl group using tert-(butoyxcarbonyloxyimino)-2-phenylacetonitrile (BOCxe2x80x94ON) and benzyloxycarbonyl group using benzylchloroformate to afford 26-2. Condensation of the carboxylic acid group of 26-2 with N-methoxy-N-methyl amine using a coupling agent such as 1,3-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or the like affords the corresponding amide 26-3. Addition of methylmagnesium bromide affords the acetylpiperazine 26-4. The carbonyl of 26-4 is reduced using sodium borohydride to give alcohol 26-5. Treatment of 26-5 with zinc azide pyridine complex in the presence of triphenylphosphine in toluene affords azido compound 26-6. Reduction of the azide to the corresponding amine by treatment with triphenylphosphine in aqueous THF gives the desired amine 26-7. Alternatively, the azide can be reduced by hydrogenation over a catalyst. 
The preparation of 2-(piperazin-2-yl)ethylamino-4-[benzimidazol-1-yl]pyrimidines such as 27-3 within the scope of the instant invention is detailed in Scheme 27. Sulfone 27-1 described in Scheme 7 can be reacted with a piperazine-substituted alkylamines such as 27-2 in dimethyformamide, dimethylsulfoxide, toluene, 1-methyl-2-pyrrolidinone, isopropanol or other suitable solvent with or without heating to give the N-benzyloxycarbonylprotected heterocycle 27-3. Alternatively, the (piperidin-3-yl)ethylamino can be affixed to the pyrimidine ring prior to the benzimidazole as described in Scheme 3, Scheme 6 and Scheme 8. 
The preparation of 2-(piperazin-2-yl)ethylamino-4-[benzimidazol-1-yl]pyrimidines such as 28-7 within the scope of the instant invention is detailed in Scheme 23. Removal of the tert-butyloxycarbonyl protecting group of 28-1 via hydrolysis using trifluoroacetic acid affords the mono-deprotected compound 28-2 within the scope of the instant invention. Subsequent acylation with an isocyanate 28-3 in pyridine gives 28-4. Alternatively, acylation can be carried out using an acid chloride or another acid halide, or other acylating agents such as acid anhydrides, esters, chloroformates, alkylsulfonyl halides, arylsulfonyl halides in pyridine or in a non-protic solvent such as methylene chloride, chloroform, tetrahydrofuran, toluene or the like in the presence of a tertiary amine base. Additionally, acylation can be carried out with an acid employing a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1,3-dicyclohexylcarbodiimide or the like. Alternatively, the secondary amine of the piperazine of compound 28-2 may be alkylated as described in Scheme 24 or arylated as described in Scheme 25. Deprotection of the benzyloxycarbonyl group can be effected by HBr in acetic acid to afford 28-5. Alkylation of 28-5 can be achieved by condensation with an aldehyde 28-6 followed by reduction using sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or the like. Alternatively, the secondary amine of compound 28-5 can be acylated, alkylated or arlated as described above. Alternatively, modification of the piperazine-substituted-ethylamine can be carried out prior to incorporation onto the pyrimidine ring of the instant invention.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims, which follow, and that such claims be interpreted as broadly as is reasonable.